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New therapy for chronic intestinal inflammation by regulating mucosal immune responses

Research Project

Project/Area Number 11470138
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionKeio University

Principal Investigator

HIBI Toshifumi  Keio University, School of Medicine, Professor, 医学部, 教授 (50129623)

Co-Investigator(Kenkyū-buntansha) WATANABE Mamoru  Tokyo Medical & Dental Univ., Dept.of Medicine, Professor, 医学部, 教授 (10175127)
KOYASU Shigeo  Keio University, School of Medicine, Professor, 医学部, 教授 (90153684)
ISHIKAWA Hiromichi  Keio University, School of Medicine, Professor, 医学部, 教授 (20051667)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2000: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1999: ¥9,700,000 (Direct Cost: ¥9,700,000)
Keywordsinterleukin-7 / interleukin-7 receptor / mucosal immunology / transgenic mice / cytokine / inflammatory bowel disease / knock-out mice / T lymphocytes
Research Abstract

Chronic inflammatory bowel disease (IBD) is a inflammatory disorder of the intestine with unknown etiology, and therefore no specific treatment is available for the management of IBD.We have already reported that interleukin-7 (IL-7) is produced by intestinal epithelial cells, especially goblet cells, as well as stromal cells in thymus and bone marrow, and the IL-7/IL-7 receptor (IL-7R) system plays an important role in regulating the T lymphocyte proliferation, activation and function in the intestine (J Clin Invest 95 : 2945, 1995). Based on these findings, we generated IL-7 transgenic mice and found that these mice developed chronic colitis resembling human ulcerative colitis, and demonstrated the involvement mucosal CD4 positive T lymphocytes in the intestinal inflammation (J Exp Med 187 : 389, 1998). Moreover, we demonstrated that CD 4 positive T lymphocytes with particular Vβ usage were preferentially activated in the inflamed lesions of CD (Clin Immunol Immunopathol 78 : 130, 1996).
In this study, we evaluated the therapeutic effect of a synthetic mimetic of CD4 designed to mimic both the sequence and conformation of complementarity-determining region 3 of murine CD4 V1 domain (rD-mPGPtide) in a mouse colitis model using immunization with 2,4,6-trinitrobenzene sulfonic acid (TNB). Adiministration of the rD-mPGPtide but not control scrambled peptide could suppress severe inflammation in the chronic colitis mouse model (Eur J Immunol 29 : 355, 1999).
Based on the results of this study, we are now developing the new therapeutic approach targeting the activated mucosal immune cells, i.e., diphtheria toxin conjugated IL-7 and Saporin conjugated anti-Mac-1 antibody. These specific immune therapy may provide the potential therapeutic advantages in the treatment of human IBD.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (35 results)

All Other

All Publications (35 results)

  • [Publications] Inoue N et al.: "Restricted VH gene usage in lamina propria B cells that produced anticolon antibody from patients with ulcerative colitis."Gastroenterology. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kanai T et al.: "IL-18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease."Gastroenterology. 119. 1514-1523 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takaishi H et al.: "Circulating autoantibodies against purified colonic mucin in ulcerative colitis."J Gastroenterol. 35. 20-27 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Watanabe M et al.: "Mucosal IL-7-mediated immune responses in chronic colitis - IL-7 transgenic mouse model -"Immunol Res. 20. 251-259 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakazawa A et al.: "Functional expression of a costimulatory molecule CD86 on epithelial cells in the inflamed colonic mucosa."Gastroenterology. 117. 536-545 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okamoto S et al.: "A synthetic mimetic of CD4 is able to suppress disease in a rodent model of immune colitis."Eur J Immunol. 29. 355-366 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Watanabe M et al.: "Bioregulation and its Disorders in the Gastrointestinal Tract"Blackwell Science KK. 10 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Watanabe M et al.: "Gastrointestinal Function"Excepta Medica KK. 9 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Suzuki k, Oida T, Hamada H, Hitotsumatsu O, Watanabe M, Hibi T, Yamamoto H, Kubota E, Kaminogawa S and Ishikawa H: "Gut cryptopatches : Direct evidence of extrathymic anatomical sites for intestinal T lymphoiesis"Immunitiy. 13. 691-702 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takaishi H, Ohara S, Hotta K, Yajima T, Kanai T, Inoue N, Iwao Y, Watanabe M, Ishii H and Hibi T: "Circulating autoantibodies against purified colonic mucin in ulcerative colitis."J Gastroenterol. 35. 20-27 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kanai T, Watanabe M, Nakazawa A, Yajima T, Yamazaki M, Ishii H and Hibi T: "Regulatory Effect of interleukin-4 and interleukin-13 on colon cancer cell adhesion."Br J Cancer. 82. 1717-1723 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kashiwagi K, Watanabe M, Mukai M and and Hibi T: "Microsatellite instability in the mucosa with chronic gastritis is a predictable marker for progression from gastritis to adenoma and well-differentiated adenocarcinoma."Br J Cancer. 82. 1814-1818 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Naganuma M, Iwao Y, Inoue N, Hisamatsu T, Imaeda H, Ishii H, Kanai T, Watanabe M and Hibi T: "Analysis of clinical course and long term prognosis of surgical and non-surgical patients with intestinal Behcet's disease."Am J Gastroenterol. 95. 2848-2851 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kanai T, Watanabe M, Nakamaru K, Okazawa A, Okamoto M, Naganuma M, Ishii H, Ikeda M, Kurimoto M, and Hibi T: "IL-18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease."Gastroenterology. 119. 1514-1523 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Okamoto S, Watanabe M, Yamazaki M, Yajima T, Hayashi T, Ishii H, Yamada T, Watanabe N, B A.Jameson and Hibi T: "A synthetic mimetic of CD4 is able to suppress disease in a rodent model of immune colitis."Eur J Immunol. 29. 355-366 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Yonamine Y, Watanabe M, Kinjo F and Hibi T: "Generation of MHC class I-restricted cytotoxic T cell lines and clones against colonic epithelial cells from ulcerative colitis."J Clin Immunol. 19. 77-85 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nakazawa A, Watanabe M, Kanai T, Yajima T, Yamazaki M, Ogata H, Ishii H, Azuma M and Hibi T: "Functional expression of a costimulatory molecule CD86 on epithelial cells in the inflamed colonic mucosa."Gastroenterology. 117. 536-545 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hisamatsu T, Watanabe M, Ogata H, Ezaki T, Kanai T, Hozawa S, Ishii H and Hibi T: "Interferon-inducible gene family 1-8U expression in colitis-associated colon cancer and severely inflamed colonic mucosa in ulcerative colitis."Cancer Research. 59. 5927-5931 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Watanabe M, Ueno Y, Yamazaki M and Hibi T: "Mucosal IL-7-mediated immune responses in chronic colitis-IL-7 transgenic mouse model-"Immunol Res. 20. 251-259 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kohyama M, Nanno M, Kawaguchi-Miyashita M, Shimada S, Watanabe M, Hibi T, Kaminogawa S and Ishikawa H: "Cytolytic and IFN-γ-producing activities of γ^δ T cells in the mouse intestinal epithelium are TCR-b chain dependent."Proc Natl Acad Sci, USA. 96. 7451-7455 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kanai T et al: "Interleukin-18 and Crohn's Disease."Digestion. 63(suppl 1). 37-42 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Suzuki K et al: "Gut cryptopatches : Direct evidence of extrathymic anatomical sites for intestinal T lymphoiesis. Immunitiy"Immunitiy. 13. 691-702 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kanai T et al: "IL-18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease."Gastroenterology. 119. 1514-1523 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kanai T et al: "Regulatory effect of interleukin-4 and interleukin-13 in colon cancer cell adhesion."Br J Cancer. 82. 1717-1723 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Okamoto S et al: "A synthetic mimetic of CD4 is able to suppress disease in a rodent model of immune colitis."Eur J Immunol. 29. 355-366 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Watanabe M et al: "Mucosal IL-7-mediated immune responses in chronic colitis-IL-7 transgenic mouse model-"Immunol Res. 20. 251-259 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Watanabe M et al: "Bioregulation and its Disorders in the Gastrointestinal Tract."Blackwell Science K.K.. 10 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Watanabe M et al: "Interleukin-7 transgenic mice develop chronic colitis with decrease of interleukin-7 protein accumulation in the colonic mucosa"J Exp Med. 187. 389-402 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Okamoto S et al: "A synthetic mimetic of CD4 is able to suppress disease in a rodent model of immune colitis"Eur J Immunol. 29. 355-366 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Nakazawa A et al: "Functional expression of a costimulatory molecule CD86 on epithelial cells in the inflamed colonic mucosa"Gastroenteology. 117. 536-545 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hisamatsu T et al: "IFN-inducible gene family 1-8U expression in colitis-associated colon cancer and severely inflamed colonic mucosa in ulcerative colitis"Cancer Res. 59. 5927-5931 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kohyama M et al: "Cytolytic and IFN-γ-producing activities of γδ T cells in the mouse intestinal epithelium are TCR-β chain dependent"Proc Natl Acad Sci,USA.. 96. 7451-7455 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Watanabe M et al: "Mucosal IL-7-mediated immune responses in chronic colitis-IL-7 transgenic mouse model-"Immunol Res.. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Watanabe M et al: "Gastrointestinal Function"Excepta Medica. 9 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Watanabe M et al: "Bioregulation and its Disorders in the Gastrointestinal Tract"Blackwell Science KK. 10 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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